Heart failure is a growing public health problem in the United States. Currently, five million people suffer from heart failure (1) and despite considerable advances in pharmacological therapy, device technology and heart transplantation, mortality associated with heart failure increased by twenty percent from 1993 to 2003. Nearly one in three adults has hypertension in the United States (47). Seventy four percent who have congestive heart failure have blood pressure higher than 140/90 mmHg (1). The cause of heart failure is predominantly ischemic disease in non African-Americans but is related primarily to hypertension in African-Americans (48). Thus, hypertensive heart failure is still a clinical problem despite advances in anti-hypertensive agents.
Angiotensin I converting enzyme inhibitors and angiotensin II type 1 receptor blockers (ARB) are the clinical treatments for patients with heart failure (2). Because many of the signaling events associated with heart failure, including the rennin-angiotensin system, involve activation of protein kinase C (PKC) (3-5), it is of interest to determine whether PKC should be targeted for the development of new therapeutics.
The isozyme εPKC is of particular interest. Several studies report that the level and activity of εPKC increase in cardiac hypertrophy (3, 6). In transgenic mice, overexpression of the active form of εPKC induces eccentric hypertrophy and reduces cardiac functions, leading to heart failure (7, 8). In contrast, selective expression of an εPKC-activating peptide in cardiac myocytes induces concentric hypertrophy with improved cardiac function, while expression of an εPKC-inhibiting fragment results in eccentric hypertrophy and heart failure in a gene dose-dependent manner (9, 10). Finally, mice lacking εPKC have normal cardiac function (11). Thus, conflicting data on the role of εPKC in heart failure have been obtained using genetically manipulated mice and the possible effect of εPKC during heart development further complicates their interpretation. Selective pharmacological agents that regulate εPKC during the transition to heart failure may be better suited to determine the role of εPKC in heart failure.
Isozyme-selective εPKC inhibiting and activating peptides have been previously described (12). These regulators were developed based on the observation that the interaction of each PKC isozyme with its anchoring protein, the receptor for activated C-kinase (RACK), is required for its functions upon activation (13). The εPKC isozyme inhibiting peptide, εV1-2, corresponds to a sequence in the RACK-binding site on this isozyme, and the selective εPKC isozyme activating peptide, ΨεRACK, is derived from a sequence in εPKC that shares homology with its RACK (9, 12). These peptides are linked to membrane permeable peptides, TAT47-57, to enable their effective intracellular delivery (14, 15) and are therefore useful pharmacological tools.
Strategies and treatment methods to alter the progress of heart failure are desired in the art.
The foregoing examples of the related art and limitations related therewith are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent to those of skill in the art upon a reading of the specification and a study of the drawings.